We have shown in pilot experiments that low doses of veratrine given intravenously to anesthetized dogs increase the threshold for electrically induced ventricular fibrillation before and during acutely induced myocardial ischemia and do not cause ectopic impulse formation. Furthermore, using microelectrode techniques, we have demonstrated a definite threshold for repetitive responses (TRR) induced by veratrine. In studies carried out on the isolated canine right bundle branch with concentrations of veratrine below the TRR, the drug produced significant changes in repolarization, conduction, and automaticity. Our preliminary results indicate that veratrine may possess a unique set of electrophysiologic properties that make it suitable as an antifibrillatory agent. The objective of this proposal is to study further the effects of veratrine at concentrations below the TRR bot in the intact heart an in isolated portions of the intraventricular conduction system. The investigation of the intact heart will include determination of atrioventricular conduction times and refractory periods and determination of conduction velocity in the Purkinje system and ventricular muscle, before and after administration of veratrine. The investigation of isolated tissue is designed to clarify the effects of veratrine on resting transmembrane potential, membrane excitability and membrane responsiveness, and the consequent changes in conduction velocity. In addition, we will determine the effects of the drug on the relationship between the effective refractory period and the action potential duration and on conduction at the Purkinje fiber - ventricular muscle junction. It is anticipated that these studies will provide basic new electrophysiologic information that may explain the mechanisms by which veratrine protects the ventricle from fibrillation. We hope, thereby, that our understanding of the genesis and therapy of arrhythmias, in general, will be enhanced.